The present invention relates to novel benzimidazoles, methods for making them, pharmaceutical compositions comprising them, and their use as, inter alia, antithrombotic agents.
The present invention relates to benzimidazoles of general formula 
the tautomers, the stereoisomers, the mixtures thereof, the prodrugs, the derivatives thereof which contain a group which is negatively charged under physiological conditions instead of a carboxy group, and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable properties.
The compounds of the above general formula I wherein Ra denotes a straight-chained C1-3-alkyl group which is substituted in the 1 position by a pyrrolidinocarbonyl or 2,5-dihydropyrrolocarbonyl group optionally substituted by a C1-3-alkyl group and by an amino group monosubstituted by a cyano-C1-4-alkyl group, and/or Rc denotes a cyano group or a 1,2,4-oxadiazol-3-yl group substituted in the 5 position by a C1-3-alkyl or phenyl group, while the phenyl substituent may be substituted by a fluorine, chlorine or bromine atom or by a C1-3-alkyl group, are valuable intermediate products for preparing the other compounds of general formula I, and the compounds of the above general formula I wherein Rc denotes one of the following amidino groups, and the tautomers, stereoisomers, mixtures thereof, the prodrugs, the derivatives thereof which contain a group which is negatively charged under physiological conditions instead of a carboxy group, and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic salts, and the stereoisomers thereof, have valuable pharmacological properties, particularly an antithrombotic activity.
In the above general formula
Ra denotes a straight-chained C1-3-alkyl group wherein the hydrogen atoms may be wholly or partially replaced by fluorine atoms and which is substituted in the 1 position
by a pyrrolidinocarbonyl or 2,5-dihydropyrrolocarbonyl group optionally substituted by a C1-3-alkyl group and
by an amino group which is monosubstituted by a carboxy-C1-4-alkyl, cyano-C1-4-alkyl or tetrazolyl-C1-4-alkyl group,
or by a C1-3-alkyl group which is terminally substituted by an N-(carboxy-C1-3-alkylaminocarbonyl)-amino group optionally substituted by a C1-3-alkyl group at one or both amino nitrogen atoms, by a carboxy-C1-3-alkoxy, N-(carboxy-C1-3-alkyl)-amino, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkyl)-amino, N-(carboxy-C1-3-alkylsulphonyl)-amino, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkylsulphonyl)-amino or tetrazolyl-C1-3-alkyl group,
Rb denotes a C1-3-alkyl group and
Rc denotes an amidino group, a cyano group or a 1,2,4-oxadiazol-3-yl group substituted in the 5 position by a C1-3-alkyl or phenyl group, while the phenyl substituent may be substituted by a fluorine, chlorine or bromine atom or by a C1-3-alkyl group.
The carboxy groups, mentioned in the above definition of the groups, may also be replaced by a group which can be converted in vivo into a carboxy group or by a group which is negatively charged under physiological conditions or
the amino and imino groups mentioned in the above definition of the groups may also be substituted by a group which can be cleaved in vivo. Such groups are described, for example, in WO 98/46576 and by N. M. Nielson et al. in International Journal of Pharmaceutics 39, 75-85 (1987).
By a group which can be converted in vivo into a carboxy group is meant for example a hydroxmethyl group, a carboxy group esterified with an alcohol wherein the alcoholic moiety is preferably a C1-6-alkanol, a phenyl-C1-3-alkanol, a C3-9-cycloalkanol, whilst a C5-8-cycloalkanol may additionally be substituted by one or two C1-3-alkyl groups, a C5-8-cycloalkanol, wherein a methylene group in the 3 or 4 position is replaced by an oxygen atom or by an imino group optionally substituted by a C1-3-alkyl, phenyl-C1-3-alkyl, phenyl-C1-3-alkoxycarbonyl or C2-6-alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C1-3-alkyl groups, a C4-7-cycloalkenol, a C3-5-alkenol, a phenyl-C3-5-alkenol, a C3-5-alkinol or phenyl-C3-5-alkinol, with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C3-8-cycloalkyl-C1-3-alkanol, a bicycloalkanol having a total of 8 to 10 carbon atoms which may additionally be substituted in the bicycloalkyl moiety by one or two C1-3-alkyl groups, a 1,3-dihydro-3-oxo-1-isobenzofuranol or an alcohol of formula
Rd-COxe2x80x94Oxe2x80x94(ReCRf)xe2x80x94OH, 
wherein
Rd denotes a C1-8-alkyl, C5-7-cycloalkyl, phenyl or phenyl-C1-3-alkyl group,
Re denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and
Rf denotes a hydrogen atom or a C1-3-alkyl group,
by a group which is negatively charged under physiological conditions is meant a group such as a tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C1-6-alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino, C1-6-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl or perfluoro-C1-6-alkylsulphonylaminocarbonyl group
and by a group which can be cleaved in vivo from an imino or amino group is meant, for example, a hydroxy group, an acyl group such as a benzoyl group optionally mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms or by C1-3-alkyl or C1-3-alkoxy groups, whilst the substituents may be identical or different, a pyridinoyl group or a C1-16-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3,3,3-trichloropropionyl or allyloxycarbonyl group, a C1-16-alkoxycarbonyl or C1-16-alkylcarbonyloxy group wherein hydrogen atoms may be wholly or partially replaced by fluorine or chlorine atoms, such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert. butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl, hexadecyloxycarbonyl, methylcarbonyloxy, ethylcarbonyloxy, 2,2,2-trichloroethylcarbonyloxy, propylcarbonyloxy, isopropylcarbonyloxy, butylcarbonyloxy, tert.butylcarbonyloxy, pentylcarbonyloxy, hexylcarbonyloxy, octylcarbonyloxy, nonylcarbonyloxy, decylcarbonyloxy, undecylcarbonyloxy, dodecylcarbonyloxy or hexadecylcarbonyloxy group, a phenyl-C1-6-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a 3-amino-propionyl group wherein the amino group may be mono- or disubstituted by C1-6-alkyl or C3-7-cycloalkyl groups and the substituents may be identical or different, a C1-3-alkylsulphonyl-C2-4-alkoxycarbonyl, C1-3-alkoxy-C2-4-alkoxy-C2-4-alkoxycarbonyl, Rd-COxe2x80x94O-(RdCRf)-Oxe2x80x94CO, C1-6-alkyl-COxe2x80x94NHxe2x80x94(RgCRh)xe2x80x94Oxe2x80x94CO or C1-6-alkyl-COxe2x80x94Oxe2x80x94(RgCRh)-(RgCRh)xe2x80x94Oxe2x80x94CO group wherein Rd to Rf are as hereinbefore defined,
Rg and Rh, which may be identical or different, denote hydrogen atoms or C1-3-alkyl groups.
Furthermore, the saturated alkyl and alkoxy moieties which contain more than 2 carbon atoms mentioned in the above definitions also include the branched isomers thereof such as the isopropyl, tert.butyl, isobutyl group, etc., for example.
Preferred compounds of general formula I mentioned above are those wherein
Rb and Rc are as hereinbefore defined and
Ra is as hereinbefore defined, with the proviso that one substituent denotes an unbranched C1-3-alkyl group or a 2,5-dihydropyrrolocarbonyl group optionally substituted by a C1-3-alkyl group,
or Ra denotes an ethyl group which is substituted in the 1 position
by a pyrrolidinocarbonyl group and
by an amino group, while the amino group is substituted by an ethoxycarbonylmethyl group which is substituted in the ethoxy moiety in the 2 position by a methoxy, dimethylamino or tolyl group, by a carboxymethyl, C3-4-alkoxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 3-(C2-3-alkoxycarbonyl)-propyl or tetrazolylmethyl group,
Rb denotes a methyl group and
Rc denotes an amidino group substituted by a benzoyl, methylbenzoyl, fluorobenzoyl group or trifluoromethylbenzoyl group or
Ra denotes an ethyl group which is substituted in the 1 position
by a pyrrolidinocarbonyl group substituted in the 2 position by a methyl group and
by an amino group, whilst the amino group is substituted by a carboxymethyl or ethoxycarbonylmethyl group,
Rb denotes a methyl group and
Rc denotes an amidino group or
Ra denotes an ethyl group which is substituted in the 1 position
by a pyrrolidinocarbonyl group and
by an amino group substituted by a carboxymethyl, C3-4-alkoxycarbonylmethyl or tetrazolylmethyl group or
by a methyl group, whilst the methyl group is substituted by a tetrazolyl, carboxymethoxy, ethoxycarbonylmethoxy, ethoxycarbonylmethylamino, N-(2-carboxyethyl)-N-methylamino, N-[2-(C1-3-alkoxycarbonyl)-ethyl]-N-methylamino, N-(carboxymethylaminocarbonyl)-N-methyl-amino, N-(C1-3-alkoxycarbonylmethylaminocarbonyl)-N-methyl-amino, N-(carboxymethylsulphonyl)-N-methyl-amino or N-(C1-3-alkoxycarbonylmethylsulphonyl)-N-methyl-amino group,
Rb denotes a methyl group and
Rc denotes an amidino group,
the tautomers, the isomers and the salts thereof.
Particularly preferred compounds of the above general formula I are the abovementioned compounds of general formula I with the exception of
(1) 2-[4-(N-phenylcarbonyl-amidino)-phenylaminomethyl]-1-methyl-5-[1-(n-butyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole and
(2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(tetrazol-5-yl-methylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,
the tautomers, the isomers and the salts thereof.
Most particularly preferred compounds of the above general formula I are those wherein
Ra denotes an ethyl group which is substituted in the 1 position
by a 2,5-dihydropyrrolocarbonyl group optionally substituted by a methyl group and by an amino group which may be substituted by a C2-4-alkoxycarbonyl-C1-4-alkyl group wherein the C2-4-alkoxy moiety is terminally monosubstituted by a methoxy, dimethylamino, phenyl or tolyl group, by a carboxy-C1-4-alkyl, cyclohexyloxycarbonyl-C1-4-alkyl or tetrazolyl-C1-4-alkyl group, or
by a C1-3-alkyl group which is terminally substituted by an N-(carboxy-C1-3-alkylaminocarbonyl)-amino or N-(C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl)-amino group optionally substituted at one or both amino nitrogen atoms by a C1-3-alkyl group, by a carboxy-C1-3-alkoxy, C1-3-alkoxycarbonyl-C1-3-alkoxy, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkyl)-amino, N-(C1-3-alkyl)-N-(C1-3-alkoxycarbonyl-C1-3-alkyl)-amino, N-(C1-3-alkyl)-N-(carboxy-C1-3-alkylsulphonyl)-amino or N-(C1-3-alkyl)-N-(C1-3-alkoxycarbonyl-C1-3-alkylsulphonyl)-amino or tetrazolyl-C1-3-alkyl group,
Rb denotes a methyl group and
Rc denotes an amidino group optionally substituted by a benzoyl, methylbenzoyl, fluorobenzoyl or trifluoromethylbenzoyl group
or Ra denotes an ethyl group which is substituted in the 1 position
by a pyrrolidinocarbonyl group and
by an amino group, whilst the amino group is substituted by an ethoxycarbonylmethyl group which is substituted in the 2 position by a methoxy, dimethylamino or tolyl group, by a carboxymethyl, propyloxycarbonylmethyl, isopropyloxycarbonylmethyl, isobutyloxycarbonylmethyl, cyclohexyloxycarbonylmethyl, 3-(C2-3-alkoxycarbonyl)-propyl or tetrazolylmethyl group,
Rb denotes a methyl group and
Rc denotes an amidino group substituted by a benzoyl, methylbenzoyl, fluorobenzoyl group or trifluoromethylbenzoyl group or
Ra denotes an ethyl group which is substituted in the 1 position
by a pyrrolidinocarbonyl group substituted in the 2 position by a methyl group and
by an amino group, whilst the amino group is substituted by a carboxymethyl or ethoxycarbonylmethyl group,
Rb denotes a methyl group and
Rc denotes an amidino group or
Ra denotes an ethyl group which is substituted in the 1 position
by a pyrrolidinocarbonyl group and
by an amino group substituted by a carboxymethyl or C3-4-alkoxycarbonylmethyl group or
by a methyl group, whilst the methyl group is substituted by a tetrazolyl, carboxymethoxy, ethoxycarbonylmethoxy, ethoxycarbonylmethylamino, N-(2-carboxyethyl)-N-methyl-amino, N-[2-(C1-3-alkoxycarbonyl)-ethyl]-N-methyl-amino, N-(carboxymethylaminocarbonyl)-N-methyl-amino, N-(C1-3-alkoxycarbonylmethylaminocarbonyl)-N-methyl-amino, N-(carboxymethylsulphonyl)-N-methyl-amino or N-(C1-3-alkoxycarbonylmethylsulphonyl)-N-methyl-amino group,
Rb denotes a methyl group and
Rc denotes an amidino group,
the tautomers, the isomers and the salts thereof.
The following may be mentioned as examples of particularly preferred compounds:
(1) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole,
(2) 2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(ethoxycarbonylmethylamino)- 1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole,
(3) (R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(isobutyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,
(4) (R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1 -(n-propyloxycarbonylmethylamino)-1-(pyrrolidinocarbonyl)-ethyl]-benzimidazole,
(5) (R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-[(R,S)-1-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole,
(6) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole and
(7) (R)-2-[4-(N-phenylcarbonylamidino)-phenylaminomethyl]-1-methyl-5-[1-(cyclohexyloxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole,
the isomers and the salts thereof.
According to the invention, the compounds of general formula I are obtained by methods known per se, for example by the following methods:
a) In order to prepare a compound of general formula I wherein Rc denotes a cyano group or a 1,2,4-oxadiazol-3-yl group substituted in the 5 position by a C1-3-alkyl or phenyl group, while the phenyl substituent may be substituted by a fluorine, chlorine or bromine atom or by a C1-3-alkyl group:
cyclising a compound of general formula 
optionally formed in the reaction mixture
wherein
Ra and Rb are as hereinbefore defined,
Rcxe2x80x2 denotes a cyano group or a 1,2,4-oxadiazol-3-yl group substituted in the 5 position by a C1-3-alkyl or phenyl group, while the phenyl substituent may be substituted by a fluorine, chlorine or bromine atom or by a C1-3-alkyl group,
Z1 and Z2, which may be identical or different, denote amino, hydroxy or mercapto groups optionally substituted by alkyl groups with 1 to 6 carbon atoms or
Z1 and Z2 together denote an oxygen or sulphur atom, an imino group optionally substituted by an alkyl group with 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group with 2 or 3 carbon atoms.
The cyclisation is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycoldimethylether, sulpholane, dimethylformamide or tetraline or in an excess of the acylating agent used to prepare the compound of general formula II, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide, for example at temperatures between 0 and 250xc2x0 C., but preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulphuryl chloride, sulphuric acid, p-toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid, acetic anhydride, N,N-dicyclohexyl-carbodiimide or optionally also in the presence of a base such as potassium ethoxide or potassium tert.butoxide. The cyclisation may, however, also be carried out without a solvent and/or condensing agent.
b) In order to prepare a compound of general formula I wherein Rc denotes an amidino group:
reacting a compound of general formula 
optionally formed in the reaction mixture
wherein
Ra and Rb are as hereinbefore defined and
Z4 denotes an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as the methylthio, ethylthio, n-propylthio or benzylthio group, with ammonia or with the salts thereof.
The reaction is conveniently carried out in a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 80xc2x0 C., with ammonia or one of its salts such as for example ammonium carbonate or ammonium acetate.
A compound of general formula III is obtained for example by reacting a corresponding cyano compound with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzylalcohol in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium salt such as triethyloxonium-tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50xc2x0 C., but preferably at 20xc2x0 C., or a corresponding nitrile with hydrogen sulphide, conveniently in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and subsequent alkylation of the thioamide formed with a corresponding alkyl or aralkyl halide.
c) In order to prepare a compound of general formula I wherein Ra contains a carboxy group and Rc is as hereinbefore defined:
Converting a compound of general formula 
wherein
Rb and Rc are as hereinbefore defined and
Raxe2x80x2 has the meanings given hereinbefore for Ra, with the proviso that Ra contains a group which can be converted into a carboxy group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis,
by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis into a compound of general formula I wherein Ra contains a carboxy group.
A group which may be converted into a carboxy group may be, for example, a carboxyl group protected by a protecting group such as the functional derivatives thereof, e.g. the unsubstituted or substituted amides, esters, thioesters, trimethylsilylesters, orthoesters or iminoesters thereof, which are conveniently converted into a carboxyl group by hydrolysis,
the esters thereof with tertiary alcohols, e.g. the tert.butyl ester, which are conveniently converted into a carboxyl group by treatment with an acid or thermolysis, and
the esters thereof with aralkanols, e.g. the benzyl ester, which are conveniently converted into a carboxyl group by hydrogenolysis.
The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or the mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures between xe2x88x9210 and 120xc2x0 C., e.g. at temperatures between room temperature and the boiling temperature of the reaction mixture.
If a compound of formula IV for example contains the tert.butyl or tert.butyloxycarbonyl group, this may also be cleaved by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane, preferably at temperatures between xe2x88x9210 and 120xc2x0 C., e.g. at temperatures between 0 and 60xc2x0 C., or also thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40 and 120xc2x0 C.
If a compound of formula IV contains the benzyloxy or benzyloxycarbonyl group, for example, this may also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50xc2x0 C., e.g. at room temperature, and at a hydrogen pressure of 1 to 5 bar.
d) In order to prepare a compound of general formula I wherein Rc denotes an amidino group which is substituted by a group which can be cleaved in vivo:
reacting a compound of general formula 
wherein
Ra and Rb are as hereinbefore defined, with a compound of general formula
Z5-R9xe2x80x83xe2x80x83(VII), 
wherein
R9 denotes the acyl group of one of the abovementioned groups which can be cleaved in vivo and
Z5 denotes a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a p-nitrophenyl group.
The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydro furan, toluene, dioxane, dimethylsulphoxide or dimethylformamide optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20xc2x0 C. and the boiling temperature of the solvent used.
With a compound of general formula VII wherein Z5 denotes a nucleofugic leaving group, the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone/water, dimethylformamide or dimethylsulphoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tert.butoxide or N-ethyl-diisopropylamine at temperatures between 0 and 60xc2x0 C.
e) In order to prepare a compound of general formula I wherein Rc denotes one of the abovementioned amidino groups: catalytic hydrogenation of a compound of general formula 
wherein
Ra and Rb are as hereinbefore defined and
Rcxe2x80x3 denotes a 1,2,4-oxadiazol-3-yl group substituted in the 5 position by a C1-3-alkyl or phenyl group, wherein the phenyl substituent may be substituted by a fluorine, chlorine or bromine atom or by a C1-3-alkyl group, and if necessary subsequent hydrolysis of a compound thus obtained.
The catalytic hydrogenation is preferably carried out in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethanol/glacial acetic acid, ethyl acetate, dioxane or dimethylformamide in the presence of a hydrogenation catalyst such as palladium/charcoal, preferably at temperatures between 0 and 50xc2x0 C., e.g. at room temperature, and at a hydrogen pressure of 1 to 5 bar.
The hydrolysis which may follow is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures between xe2x88x9210 and 120xc2x0 C., e.g. at temperatures between room temperature and the boiling temperature of the reaction mixture.
f) In order to prepare a compound of general formula I wherein Ra denotes an amino-C1-3-alkyl group in which the amino group is monosubstituted by a carboxy-C1-4-alkyl or tetrazolyl-C1-4-alkyl group:
alkylating a compound of general formula 
wherein
Rb and Rc are as hereinbefore defined and
Raxe2x80x3 denotes an amino-C1-3-alkyl group, with a compound of general formula
Raxe2x80x2xe2x80x3-Z7xe2x80x83xe2x80x83(X) 
wherein
Raxe2x80x2xe2x80x3 denotes a carboxy-C1-4-alkyl or tetrazolyl-C1-4-alkyl group and
Z7 denotes a nucleofugic leaving group such as a halogen atom or a sulphonic acid ester group, e.g. a chlorine, bromine or iodine atom, or a p-nitrophenyl group.
The alkylation is conveniently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide or acetone, optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which may simultaneously also act as solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between xe2x88x9230 and 100xc2x0 C., but preferably at temperatures between xe2x88x9210 and 80xc2x0 C.
If according to the invention a compound of general formula I is obtained wherein Ra contains a carboxy group, this may subsequently be converted by esterification into a corresponding compound wherein Ra contains an esterified carboxy group, and/or
if a compound of general formula I is obtained wherein Ra contains an esterified carboxy group, this may subsequently be converted by transesterification into a corresponding compound wherein Ra contains another esterified carboxy group, and/or
if a compound of general formula I is obtained wherein Ra contains a cyano group, this may subsequently be converted into a corresponding compound wherein Ra contains a tetrazolyl group.
The subsequent esterification is carried out with a corresponding alcohol, usefully in a solvent or mixture of solvents such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, but preferably in an excess of the alcohol used, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexyl carbodiimide, N,Nxe2x80x2-dicyclohexyl carbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-carbonyldiimidazole or N,Nxe2x80x2-thionyldiimidazole, triphenylphosphine/carbon tetrachloride or triphenylphosphine/diethyl azodicarboxylate, optionally in the presence of a base such as potassium carbonate, N-ethyl-diisopropylamine or N,N-dimethylamino-pyridine, conveniently at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 80xc2x0 C., or with a corresponding halide in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide or acetone, optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which may also serve as solvent at the same time, or optionally in the presence of silver carbonate or silver oxide at temperatures between xe2x88x9230 and 100xc2x0 C., but preferably at temperatures between xe2x88x9210 and 80xc2x0 C.
The subsequent transesterification is carried out with a corresponding alcohol, conveniently in a solvent or mixture of solvents such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, but preferably in an excess of the alcohol used, conveniently in the presence of an acid such as hydrochloric acid or in the presence of a compound such as 2,8,9-trimethyl-1-phospha-2,5,8,9-tetraazabicyclo[3.3.3]undecane at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 80xc2x0 C.
The subsequent conversion of a cyano group into a tetrazolyl group is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures between 80 and 150xc2x0 C., preferably at 120 and 130xc2x0 C. The hydrazoic acid needed is conveniently liberated during the reaction from an alkali metal azide, e.g. from sodium azide, in the presence of a weak acid such as ammonium chloride. The reaction may also take place with another salt or derivative of hydrazoic acid, preferably with aluminium azide or tributyl tin azide, the tetrazole compound optionally obtained in this way being liberated from the salt contained in the reaction mixture by acidification with a dilute acid such as 2N hydrochloric acid or 2N sulphuric acid.
In the reactions described hereinbefore, any reactive groups present such as carboxy, amino or alkylamino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and
protecting groups for an amino or alkylamino group may be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether cleavage, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100xc2x0 C., preferably at temperatures between 10 and 50xc2x0 C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved hydrogenolytically, for example, with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50xc2x0 C., but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
A methoxybenzyl group may also be cleaved in the presence of an oxidant such as cerium(IV)ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile/water at temperatures between 0 and 50xc2x0 C., but preferably at room temperature.
A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisol.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50xc2x0 C.
An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(triphenylphosphine)-palladium(O), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100xc2x0 C., preferably at room temperature and under inert gas, or by treating with a catalytic amount of tris-(triphenylphosphine)-rhodium(I)chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70xc2x0 C.
The compounds of general formulae II to X used as starting materials, some of which are known from the literature, are obtained by methods known from the literature, and moreover their preparation is described in the Examples.
The chemistry of the compounds of general formula II is described for example by Jack Robinson in J. Chem. Soc. 1941, 744, that of the benzimidazoles is described by Katritzky and Rees in Comprehensive Heterocyclic Chemistry, Oxford, Pergamon Press, 1984, by Schaumann in Hetarene III, Methoden der organischen Chemie (Houben-Weyl), 4th edition, published by Thieme, Stuttgart 1993.
Thus, for example, a compound of general formula II is obtained by acylating a corresponding o-diamino compound with a corresponding reactive acyl derivative,
a compound of general formulae III, IV, VI, VIII and IX is obtained by cyclising a corresponding, substituted compound according to process a) and if necessary subsequently converting a cyano compound thus obtained into the desired starting compound using known methods.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers.
Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in xe2x80x9cTopics in Stereochemistryxe2x80x9d, Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (xe2x88x92)-menthol and an optically active acyl group in amides, for example, may be a (+)-or (xe2x88x92)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
Moreover, if the new compounds of formula I contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof.
Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
As already mentioned, the new compounds of general formula I and the salts thereof have valuable properties. Thus, the compounds of general formula I wherein Rc denotes a cyano group are valuable intermediate products for preparing the other compounds of general formula I, and the compounds of general formula I wherein Rc denotes one of the amidino groups mentioned hereinbefore, and the tautomers, the stereoisomers and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an antithrombotic effect which is preferably based on influencing thrombin or factor Xa, e.g. on an inhibitory effect on thrombin or factor Xa, on an effect of prolonging the aPTT time and an inhibitory effect on related serine proteases such as e.g. trypsin, urokinase factor VIIa, factor IX, factor XI and factor XII.
For example, the following compounds:
A=2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(ethoxycarbonylmethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-dihydrochloride,
B=(R)-2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-[(R,S)-2-methyl-pyrrolidinocarbonyl]-ethyl]-benzimidazole-dihydrochloride and
C=(2) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(2,5-dihydropyrrolocarbonyl)-ethyl]-benzimidazole-dihydrochloride
were investigated as follows for their effects on prolonging the aPTT time:
Materials: plasma, from human citrated blood. PTT reagent, Boehringer Mannheim (524298), Calcium solution (0.025 mol/l), Behring Werke, Marburg (ORH 056/57), Diethylbarbiturate acetate buffer, Behring Werke, Marburg (ORWH 60/61), Biomatic B10 coagulometer, Desaga, Wiesloch.
Method:
The aPTT time was determined using a Biomatic B10 coagulometer made by Messrs. Desaga.
The test substance was placed in the test tubes prescribed by the manufacturer together with 0.1 ml of human citrated plasma and 0.1 ml of PTT reagent. The mixture was incubated for three minutes at 37xc2x0 C. The clotting reaction was started by the addition of 0.1 ml of calcium solution. The time is measured using the apparatus from the addition of the calcium solution up to the clotting of the mixture. Mixtures to which 0.1 ml of DBA buffer were added were used as the controls.
According to the definition, a dosage-activity curve was used to determine the effective concentration of the substance, i.e. the concentration at which the aPTT time is doubled compared with the control.
The Table which follows contains the results found:
The compounds prepared according to the invention are well tolerated since no toxic side effects could be detected at therapeutic doses; moreover, the corresponding prodrugs, for example the compounds of Examples 1(6), 2, 3(2) and 3(5), exhibit good oral resorption.
In view of their pharmacological properties the new compounds and the physiologically acceptable salts thereof are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as for example the treatment of deep leg vein thrombosis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, for preventing coronary thrombosis, stroke and the occlusion of shunts. In addition, the compounds according to the invention are suitable for antithrombotic support in thrombolytic treatment, such as for example with rt-PA or streptokinase, for preventing long-term restenosis after PT(C)A, for preventing metastasis and the growth of clot-dependent tumours and fibrin-dependent inflammatory processes, e.g. in the treatment of pulmonary fibrosis.
The dosage required to achieve such an effect is appropriately 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg by intravenous route, and 0.1 to 50 mg/kg, preferably 0.3 to 30 mg/kg by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.